Non-Hodgkin lymphoma

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Follicular lymphoma

BR

BR: Bendamustine, Rituximab

Regimen

• Rituximab (Rituxan) 375 mg/m2 IV on day 1

Cycle 1 is started 7 days after the first dose of rituximab

• Bendamustine (Treanda) 90 mg/m2 IV over 30 minutes on days 1 & 2 of cycles 1-4
• Rituximab (Rituxan) 375 mg/m2 IV on day 1 of cycles 1-5

28-day cycles x 5 cycles

References

1. Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, Josten KM, Dürk H, Rost A, Neise M, von Grünhagen U, Chow KU, Hansmann ML, Hoelzer D, Mitrou PS. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005 May 20;23(15):3383-9. link to original article contains protocol PubMed

BVR

BVR: Bendamustine, Velcade, Rituximab

Regimen (Friedberg, et al. 2011)

• Bendamustine (Treanda) 90 mg/m2 IV over 30-60 minutes on days 1 & 4, given last
• Bortezomib (Velcade) 1.3 mg/m2 IV push on days 1, 4, 8, 11, given first
• Rituximab (Rituxan) 375 mg/m2 IV on day 1, given after bortezomib and before bendamustine

28-day cycles x 6 cycles

Supportive medications:

• Premedications, antiemetic therapy, and growth factor support per institutional guidelines
• No routine antibiotic or antiviral prophylaxis was given

Alternate regimen (Fowler, et al. 2011)

• Bendamustine (Treanda) 50-90 mg/m2 IV over 60 minutes on days 1 & 2, given after bortezomib and before rituximab
• Bortezomib (Velcade) 1.6 mg/m2 IV on days 1, 8, 15, 22, given first
• Rituximab (Rituxan) 375 mg/m2 IV on days 1, 8, 15, 22 of cycle 1, then 375 mg/m2 IV on day 1 of cycles 2-5; given last

35-day cycles x 5 cycles

Supportive medications:

• Antiviral prophylaxis at physician discretion

References

1. Friedberg JW, Vose JM, Kelly JL, Young F, Bernstein SH, Peterson D, Rich L, Blumel S, Proia NK, Liesveld J, Fisher RI, Armitage JO, Grant S, Leonard JP. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood. 2011 Mar 10;117(10):2807-12. Epub 2011 Jan 14. link to original article contains protocol PubMed
2. Fowler N, Kahl BS, Lee P, Matous JV, Cashen AF, Jacobs SA, Letzer J, Amin B, Williams ME, Smith S, Saleh A, Rosen P, Shi H, Parasuraman S, Cheson BD. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011 Sep 1;29(25):3389-95. Epub 2011 Aug 1. link to original article contains protocol PubMed

Cyclophosphamide (Cytoxan)

Regimen

• Cyclophosphamide (Cytoxan) 100 mg/m2 PO daily, with dose modifications according to WBC and platelet count as listed in table 1 of Peterson, et al. 2003

References

1. Peterson BA, Petroni GR, Frizzera G, Barcos M, Bloomfield CD, Nissen NI, Hurd DD, Henderson ES, Sartiano GP, Johnson JL, Holland JF, Gottlieb AJ. Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol. 2003 Jan 1;21(1):5-15. link to original article contains protocol PubMed

CHOP -> Tositumomab & I-131 (Bexxar)

CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Regimen

CHOP

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV on day 1
• Prednisone (Sterapred) 100 mg PO on days 1-5

21-day cycles x 6 cycles

Supportive medications:

• Allopurinol (Aloprim) 300 mg PO daily for patients with bulky disease

Tositumomab & I-131 (Bexxar) dosimetric step

• On Day 0, infusions of:
  • Tositumomab 450 mg IV over 1 hour
  • Tositumomab 35 mg labeled with 5 mCi of Iodine-131 IV over 20 minutes
  • First scan of whole body dosimetry & redistribution
• Day 2, 3, or 4: Second scan of whole body dosimetry & redistribution
• Day 6 or 7: Third scan of whole body dosimetry & redistribution

Tositumomab & I-131 (Bexxar) therapeutic step

• Any day from day 7-14, infusions of:
  • Tositumomab 450 mg IV over 1 hour
  • Tositumomab 35 mg labeled with an individually calculated dose of Iodine-131 that will provide 75 cGy of radiation to the total body IV over 20 minutes
    • 65 cGy total body dose used for patients with platelet counts of 100-150,000/mm3

Calculated dose of I-131 is based on information from serial total-body gamma-camera counts

Supportive medications:

• Acetaminophen (Tylenol) 650 mg PO as premedication for tositumomab
• Diphendyramine (Benadryl) 50 mg PO as premedication for tositumomab
• Potassium iodide 4 drops PO TID, Lugol solution 20 drops PO TID, or potassium iodide tablets 130 mg PO daily starting at least 24 hours before the dosimetric step and continuing for 14 days after the therapeutic infusion

References

1. Press OW, Unger JM, Braziel RM, Maloney DG, Miller TP, LeBlanc M, Gaynor ER, Rivkin SE, Fisher RI. A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911. Blood. 2003 Sep 1;102(5):1606-12. Epub 2003 May 8. link to original article contains protocol PubMed
2. Press OW, Unger JM, Braziel RM, Maloney DG, Miller TP, Leblanc M, Fisher RI; Southwest Oncology Group. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin's lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol. 2006 Sep 1;24(25):4143-9. Epub 2006 Aug 8. link to original article PubMed

FCMR

FCMR: Fludarabine, Cyclophosphamide, Mitoxantrone, Rituximab

Regimen

• Fludarabine (Fludara) 25 mg/m2 IV over 30 minutes on days 1-3
• Cyclophosphamide (Cytoxan) 200 mg/m2 IV over 4 hours on days 1-3
• Mitoxantrone (Novantrone) 8 mg/m2 IV over 30 minutes on day 1
• Rituximab (Rituxan) 375 mg/m2 IV on day 0

28-day cycles x 4 cycles

References

1. Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. link to original article contains protocol PubMed

Fludarabine (Fludara) & Rituximab (Rituxan)

Regimen

• Rituximab (Rituxan) 375 mg/m2 IV on days 1 & 4

Cycle 1 begins 72 hours after the second dose of rituximab

• Fludarabine (Fludara) 25 mg/m2 IV on days 1-5 of cycles 1-6
• Rituximab (Rituxan) 375 mg/m2 IV given 72 hours before cycle 2 day 1, 72 hours before cycle 4 day 1, and 72 hours before cycle 6 day 1
• Rituximab (Rituxan) 375 mg/m2 IV on days 1 & 4 of cycle 7

28-day cycles x 7 cycles

References

1. Czuczman MS, Koryzna A, Mohr A, Stewart C, Donohue K, Blumenson L, Bernstein ZP, McCarthy P, Alam A, Hernandez-Ilizaliturri F, Skipper M, Brown K, Chanan-Khan A, Klippenstein D, Loud P, Rock MK, Benyunes M, Grillo-Lopez A, Bernstein SH. Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol. 2005 Feb 1;23(4):694-704. link to original article contains protocol PubMed

Rituximab (Rituxan), Ibritumomab tiuxetan & Yttrium-90 (Zevalin)

Regimen

Consolidation therapy for patients in complete or partial remission after first-line therapy

• Rituximab (Rituxan) 250 mg/m2 IV on days 1 & 8
• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 14.8 MBq/kg (maximum dose of 1184 MBq) IV slow push over 10 minutes on day 8 immediately following rituximab

8-day course of therapy

Alternate regimen #1 (Witzig, et al. Aug 2002)

For patients with rituximab-refractory disease

• Rituximab (Rituxan) 250 mg/m2 IV on days 1 & 8
• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (15 MBq/kg) (maximum dose of 32 mCi/1.2 GBq) IV over 10 minutes on day 8 immediately following rituximab

8-day course of therapy

Alternate regimen #2 (Witzig, et al. May 2002)

For patients with relapsed or refractory disease

• Rituximab (Rituxan) 250 mg/m2 IV on days 1 & 8
• Ibritumomab tiuxetan 1.6 mg & Indium-111 5 mCi IV over 10 minutes on day 1
• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (15 MBq/kg) (maximum dose of 32 mCi/1.2 GBq) IV over 10 minutes on day 8 immediately following rituximab

8-day course of therapy

References

1. Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, Pohlman BL, Bartlett NL, Wiseman GA, Padre N, Grillo-López AJ, Multani P, White CA. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2002 May 15;20(10):2453-63. link to original article contains protocol PubMed
2. Witzig TE, Flinn IW, Gordon LI, Emmanouilides C, Czuczman MS, Saleh MN, Cripe L, Wiseman G, Olejnik T, Multani PS, White CA. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol. 2002 Aug 1;20(15):3262-9. link to original article contains protocol PubMed
3. Morschhauser F, Radford J, Van Hoof A, Vitolo U, Soubeyran P, Tilly H, Huijgens PC, Kolstad A, d'Amore F, Gonzalez Diaz M, Petrini M, Sebban C, Zinzani PL, van Oers MH, van Putten W, Bischof-Delaloye A, Rohatiner A, Salles G, Kuhlmann J, Hagenbeek A. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008 Nov 10;26(32):5156-64. Epub 2008 Oct 14. link to original article contains protocol PubMed

R-CHOP

R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Regimen (Hiddemann, et al. 2005)

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV on day 1
• Prednisone (Sterapred) 100 mg/m2 PO on days 1-5
• Rituximab (Rituxan) 375 mg/m2 IV on day 0

21-day cycles x 6-8 cycles

Alternate regimen (Czuczman, et al. 1999)

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV on day 1
• Prednisone (Sterapred) 100 mg/m2 PO on days 1-5
• Rituximab (Rituxan) doses given by the following schedule:
  • Rituximab (Rituxan) 375 mg/m2 IV on days -6 & -1 of cycle 1 (7 and 2 days before cycle 1 day 1)
  • Rituximab (Rituxan) 375 mg/m2 IV 2 days before cycle 3 day 1 and 2 days before cycle 5 day 1
  • Rituximab (Rituxan) 375 mg/m2 IV 8 days and 15 days after completion of cycle 6 (i.e. what would be cycle 7 days 8 & 15)

21-day cycles x 6 cycles

References

1. Czuczman MS, Grillo-López AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, Klippenstein D, Dallaire B, Varns C. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999 Jan;17(1):268-76. link to original article contains protocol PubMed
2. Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-López AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004 Dec 1;22(23):4711-6. Epub 2004 Oct 13. link to original article PubMed
3. Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, Reiser M, Metzner B, Harder H, Hegewisch-Becker S, Fischer T, Kropff M, Reis HE, Freund M, Wörmann B, Fuchs R, Planker M, Schimke J, Eimermacher H, Trümper L, Aldaoud A, Parwaresch R, Unterhalt M. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005 Dec 1;106(12):3725-32. Epub 2005 Aug 25. link to original article contains protocol PubMed

R-CVP

R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV on day 1
• Prednisone (Sterapred) 40 mg/m2 PO on days 1-5
• Rituximab (Rituxan) 375 mg/m2 IV on day 1

21-day cycles x up to 8 cycles

References

1. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, Solal-Celigny P, Offner F, Walewski J, Raposo J, Jack A, Smith P. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005 Feb 15;105(4):1417-23. link to original article contains protocol PubMed
2. Marcus R, Imrie K, Solal-Celigny P, Catalano JV, Dmoszynska A, Raposo JC, Offner FC, Gomez-Codina J, Belch A, Cunningham D, Wassner-Fritsch E, Stein G. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008 Oct 1;26(28):4579-86. Epub 2008 Jul 28. link to original article PubMed

R-FND

R-FND: Rituximab, Fludarabine, Novantrone, Dexamethasone

Regimen

Primary reference was not able to be obtained to verify this regimen

• Fludarabine (Fludara) 25 mg/m2 IV on days 1-3
• Mitoxantrone (Novantrone) 10 mg/m2 IV on day 1
• Dexamethasone (Decadron) 20 mg PO/IV on days 1-5
• Rituximab (Rituxan) 375 mg/m2 IV on day 1

28-day cycles x up to 8 cycles

Supportive medications:

• Prophylactic trimethoprim/sulfamethoxazole, acyclovir, and fluconazole

References

1. McLaughlin P, Hagemeister FB, Rodriguez MA, Sarris AH, Pate O, Younes A, Lee MS, Dang NH, Romaguera JE, Preti AH, McAda N, Cabanillas F. Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. Semin Oncol. 2000 Dec;27(6 Suppl 12):37-41. PubMed
2. P. McLaughlin, M. A. Rodriguez, F. B. Hagemeister, J. Romaguera, A. H. Sarris, A. Younes, N. H. Dang, A. Goy, F. Samaniego, M. Hess, et al. Stage IV indolent lymphoma: A randomized study of concurrent vs. sequential use of FND chemotherapy (fludarabine, mitoxantrone, dexamethasone) and rituximab (R) monoclonal antibody therapy, with interferon maintenance. 2003 ASCO Annual Meeting Abstract 2269. link to abstract
3. Hagemeister F, Cabanillas F, Coleman M, Gregory SA, Zinzani PL. The role of mitoxantrone in the treatment of indolent lymphomas. Oncologist. 2005 Feb;10(2):150-9. link to original article PubMed
4. Liu Q, Fayad L, Cabanillas F, Hagemeister FB, Ayers GD, Hess M, Romaguera J, Rodriguez MA, Tsimberidou AM, Verstovsek S, Younes A, Pro B, Lee MS, Ayala A, McLaughlin P. Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol. 2006 Apr 1;24(10):1582-9. link to original article PubMed
5. G. E. Manoukian, F. B. Hagemeister, P. McLaughlin, L. Fayad, F. Samaniego, A. Goy, J. E. Romaguera, B. Pro, F. Cabanillas, M. A. Rodriguez. Rituximab, fludarabine, mitoxantrone, and dexamethasone (R-FND) for patients with relapsed indolent B-cell lymphoma (RIL). 2010 ASCO Annual Meeting Abstract 8078. link to abstract

Rituximab (Rituxan)

Regimen

• Rituximab (Rituxan) 375mg/m2 IV weekly x 4 weeks; initial infusion rate of 50 mg/H, then increased as tolerated by 50 mg/H every 30 minutes, to a maximum rate of 300 mg/H

4-week course

Supportive medications:

• Acetaminophen (Tylenol) 650 mg PO 30 minutes prior to each dose of rituximab
• Diphendyramine (Benadryl) 50 mg PO 30 minutes prior to each dose of rituximab

Maintenance regimen (Salles, et al. 2011)

Starts 8 weeks after the last induction treatment

• Rituximab (Rituxan) 375mg/m2 IV on day 1

8-week cycles x 12 cycles

References

1. Colombat P, Salles G, Brousse N, Eftekhari P, Soubeyran P, Delwail V, Deconinck E, Haïoun C, Foussard C, Sebban C, Stamatoullas A, Milpied N, Boué F, Taillan B, Lederlin P, Najman A, Thièblemont C, Montestruc F, Mathieu-Boué A, Benzohra A, Solal-Céligny P. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood. 2001 Jan 1;97(1):101-6. link to original article contains protocol PubMed
2. Hainsworth JD, Litchy S, Burris HA 3rd, Scullin DC Jr, Corso SW, Yardley DA, Morrissey L, Greco FA. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol. 2002 Oct 15;20(20):4261-7. link to original article contains protocol PubMed
3. Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article contains protocol PubMed

Tositumomab & I-131 (Bexxar)

Regimen

Dosimetric step

• On Day 0, infusions of:
  • Tositumomab 450 mg IV over 1 hour
  • Tositumomab 35 mg labeled with 5 mCi of Iodine-131 IV over 20 minutes
  • First scan of whole body dosimetry & redistribution
• Day 2, 3, or 4: Second scan of whole body dosimetry & redistribution
• Day 6 or 7: Third scan of whole body dosimetry & redistribution

Therapeutic step

• Any day from day 7-14, infusions of:
  • Tositumomab 450 mg IV over 1 hour
  • Tositumomab 35 mg labeled with an individually calculated dose of Iodine-131 that will provide 75 cGy of radiation to the total body IV over 20 minutes
    • 65 cGy total body dose used for patients with platelet counts of 100-150,000/mm3

Calculated dose of I-131 is based on information from serial total-body gamma-camera counts

Supportive medications:

• Acetaminophen (Tylenol) 650 mg PO as premedication for tositumomab
• Diphendyramine (Benadryl) 50 mg PO as premedication for tositumomab
• Potassium iodide 2 drops PO TID starting at least 24 hours before the dosimetric step and continuing for 14 days after the therapeutic infusion; may also use Lugol’s solution or potassium iodide tablets

References

1. Kaminski MS, Zelenetz AD, Press OW, Saleh M, Leonard J, Fehrenbacher L, Lister TA, Stagg RJ, Tidmarsh GF, Kroll S, Wahl RL, Knox SJ, Vose JM. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol. 2001 Oct 1;19(19):3918-28. link to original article contains protocol PubMed
2. Kaminski MS, Tuck M, Estes J, Kolstad A, Ross CW, Zasadny K, Regan D, Kison P, Fisher S, Kroll S, Wahl RL. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med. 2005 Feb 3;352(5):441-9. link to original article contains protocol PubMed
3. Fisher RI, Kaminski MS, Wahl RL, Knox SJ, Zelenetz AD, Vose JM, Leonard JP, Kroll S, Goldsmith SJ, Coleman M. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol. 2005 Oct 20;23(30):7565-73. Epub 2005 Sep 26. link to original article PubMed
4. Tositumomab and I-131 (Bexxar) package insert

Aggressive lymphoma

CHOP

Regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV day 1
• Prednisone (Sterapred) 100 mg PO days 1-5

Q21days x 6-8 cycles

References

1. Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005 Jun 20;23(18):4117-26. link to original article contains protocol PubMed

R-CHOP

Regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV day 1
• Prednisone (Sterapred) 100 mg PO days 1-5
• Rituximab (Rituxan) 375mg/m2 IV day 1

Q21days x 6-8 cycles

References

See references for CHOP

CVP

Regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV day 1
• Prednisone (Sterapred) 40 mg/m2 PO days 1-5

Q21days x up to 8 cycles

References

1. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, Solal-Celigny P, Offner F, Walewski J, Raposo J, Jack A, Smith P. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005 Feb 15;105(4):1417-23. link to original article contains protocol PubMed

R-CVP

Regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV day 1
• Prednisone (Sterapred) 40 mg/m2 PO days 1-5
• Rituximab (Rituxan) 375mg/m2 IV day 1

Q21days x up to 8 cycles

References

See references for CVP

EPOCH

Regimen (original EPOCH protocol)

• Etoposide (Vepesid) 50 mg/m2/day (200 mg/m2 total) IV continuous infusion on days 1-4
• Prednisone (Sterapred) 60 mg/m2/day PO on days 1-5 (regimen originally was days 1-6, but now is just days 1-5)
• Vincristine (Oncovin) 0.4 mg/m2/day (1.6 mg/m2 total) (sometimes capped at maximum total dose of 2mg per cycle) IV continuous infusion on days 1-4
• Doxorubicin (Adriamycin) 10 mg/m2/day (40 mg/m2 total) IV continuous infusion on days 1-4
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 5 (regimen originally was day 6, but now is day 5)
• PCP prophylaxis (choose one)
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID 3 days per week
  • Atovaquone (Mepron) 1500mg PO daily
  • Pentamidine (Nebupent) 300 mg nebulized Q28days
• Filgrastim (Neupogen) 5 mcg/kg SQ daily start day 6 and continue until ANC >5,000/uL past nadir

Q21days x 6-8 cycles

Alternate regimen, as listed for the dose-adjusted EPOCH protocol (Wilson, et al. 2002)

• Etoposide (Vepesid) 50 mg/m2/day (200 mg/m2 total) IV continuous infusion on days 1-4
• Prednisone (Sterapred) 60 mg/m2 PO BID on days 1-5
• Vincristine (Oncovin) 0.4 mg/m2/day (1.6 mg/m2 total) (not capped in the paper, but sometimes capped at a maximum total dose of 2mg per cycle) IV continuous infusion on days 1-4
• Doxorubicin (Adriamycin) 10 mg/m2/day (40 mg/m2 total) IV continuous infusion on days 1-4
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 5

• PCP prophylaxis (choose one)
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID 3 days per week
  • Atovaquone (Mepron) 1500mg PO daily
  • Pentamidine (Nebupent) 300 mg nebulized Q28days
• Filgrastim (Neupogen) 5 mcg/kg SQ daily start day 6 and continue until ANC >5,000/uL past nadir

Q21days x 6-8 cycles

Dose-adjustments for EPOCH protocol

• Start cycle 1 as described above
• Obtain twice per week CBCs for nadir measurements
• If nadir ANC >500, increase etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• If nadir ANC <500 on 1 or 2 measurements, use same doses as last cycle
• If nadir ANC <500 on at least 3 measurements, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• And/or if nadir platelet count <25 on at least 1 measurement, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• Dose adjustments below the cycle 1 starting dose only applies to cyclophosphamide. The lowest etoposide and doxorubicin would be dosed at is the original cycle 1 dose.
• Can start new cycle Q21days if ANC >1,000 and platelets >100. If counts are below those levels, check daily CBC and continue growth factor support until counts are adequate and next cycle can start.

Historic dose adjustments for hematologic toxicity

These adjustments were in the original paper for standard EPOCH, which are much less relevant due to growth factor support.
If ANC on day 1 is:

• >1,500, full dose cyclophosphamide
• 1,000-1,500, reduce cyclophosphamide by 187 mg/m2 (equal to 25% dose reduction)
• <1,000, hold EPOCH
• If ANC nadir is <500, reduce cyclophosphamide an additional 187 mg/m2
• If ANC nadir is >500 and patient had previously been dose-reduced, increase cyclophosphamide dose by 187 mg/m2

References

1. Wilson WH, Bryant G, Bates S, Fojo A, Wittes RE, Steinberg SM, Kohler DR, Jaffe ES, Herdt J, Cheson BD, et al. EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. J Clin Oncol. 1993 Aug;11(8):1573-82 link to original article contains protocol PubMed
2. Wilson WH, Grossbard ML, Pittaluga S, Cole D, Pearson D, Drbohlav N, Steinberg SM, Little RF, Janik J, Gutierrez M, Raffeld M, Staudt L, Cheson BD, Longo DL, Harris N, Jaffe ES, Chabner BA, Wittes R, Balis F. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood. 2002 Apr 15;99(8):2685-93. link to original article contains protocol PubMed
3. Wilson WH, Dunleavy K, Pittaluga S, Hegde U, Grant N, Steinberg SM, Raffeld M, Gutierrez M, Chabner BA, Staudt L, Jaffe ES, Janik JE. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol. 2008 Jun 1;26(16):2717-24. link to original article PubMed

R-EPOCH

Regimen, based on original EPOCH protocol

• Rituximab (Rituxan) 375mg/m2 IV once per cycle (usually given as outpatient due to reimbursement issues)
• Etoposide (Vepesid) 50 mg/m2/day (200 mg/m2 total) IV continuous infusion on days 1-4
• Prednisone (Sterapred) 60 mg/m2/day PO on days 1-5 (regimen originally was days 1-6, but now is just days 1-5)
• Vincristine (Oncovin) 0.4 mg/m2/day (1.6 mg/m2 total) (sometimes capped at maximum total dose of 2mg per cycle) IV continuous infusion on days 1-4
• Doxorubicin (Adriamycin) 10 mg/m2/day (40 mg/m2 total) IV continuous infusion on days 1-4
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 5 (regimen originally was day 6, but now is day 5)
• PCP prophylaxis (choose one)
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID 3 days per week
  • Atovaquone (Mepron) 1500mg PO daily
  • Pentamidine (Nebupent) 300 mg nebulized Q28days
• Filgrastim (Neupogen) 5 mcg/kg SQ daily start day 6 and continue until ANC >5,000/uL past nadir

Q21days x 6-8 cycles

Alternate regimen, as listed for the dose-adjusted EPOCH protocol (Wilson, et al. 2002)

• Rituximab (Rituxan) 375mg/m2 IV once per cycle (usually given as outpatient due to reimbursement issues)
• Etoposide (Vepesid) 50 mg/m2/day (200 mg/m2 total) IV continuous infusion on days 1-4
• Prednisone (Sterapred) 60 mg/m2 PO BID on days 1-5
• Vincristine (Oncovin) 0.4 mg/m2/day (1.6 mg/m2 total) (not capped in the paper, but sometimes capped at a maximum total dose of 2mg per cycle) IV continuous infusion on days 1-4
• Doxorubicin (Adriamycin) 10 mg/m2/day (40 mg/m2 total) IV continuous infusion on days 1-4
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 5

• PCP prophylaxis (choose one)
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID 3 days per week
  • Atovaquone (Mepron) 1500mg PO daily
  • Pentamidine (Nebupent) 300 mg nebulized Q28days
• Filgrastim (Neupogen) 5 mcg/kg SQ daily start day 6 and continue until ANC >5,000/uL past nadir

Q21days x 6-8 cycles

Dose-adjusted R-EPOCH protocol

• Start cycle 1 as described above
• Obtain twice per week CBCs for nadir measurements
• If nadir ANC >500, increase etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• If nadir ANC <500 on 1 or 2 measurements, use same doses as last cycle
• If nadir ANC <500 on at least 3 measurements, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• And/or if nadir platelet count <25 on at least 1 measurement, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• Dose adjustments below the cycle 1 starting dose only applies to cyclophosphamide. The lowest etoposide and doxorubicin would be dosed at is the original cycle 1 dose.
• Can start new cycle Q21days if ANC >1,000 and platelets >100. If counts are below those levels, check daily CBC and continue growth factor support until counts are adequate and next cycle can start.

Historic dose adjustments for hematologic toxicity

These adjustments were in the original paper for standard EPOCH, which are much less relevant due to growth factor support.
If ANC on day 1 is:

• >1,500, full dose cyclophosphamide
• 1,000-1,500, reduce cyclophosphamide by 187 mg/m2 (equal to 25% dose reduction)
• <1,000, hold EPOCH
• If ANC nadir is <500, reduce cyclophosphamide an additional 187 mg/m2
• If ANC nadir is >500 and patient had previously been dose-reduced, increase cyclophosphamide dose by 187 mg/m2

References

See references for EPOCH

High-dose Methotrexate (MTX) & Ifosfamide

Regimen

• Methotrexate (MTX) 4000 mg/m2 IV over 4 hours on day 1
• Ifosfamide (Ifex) 1500-2000 mg/m2 IV over 3 hours on days 3-5
• Mesna (Mesnex) for prophylaxis of hemorrhagic cystitis
• Folinic acid (Leucovorin) rescue starting 24 hours after start of methotrexate infusion
• Sodium bicarbonate via IV fluid or PO routes used for urine alkalization for urine pH ?8
• Check methotrexate levels 24, 48, and 72 hours after completion of methotrexate infusion.

Methotrexate (MTX) dose adjusted for creatinine clearances <100 mL/min according to the following formula:

• Dose of methotrexate = (creatinine clearance/100) x 4000 mg/m2; the paper did not specify what method was used for calculating creatinine clearance. Patients with creatinine clearance <50 mL/min were excluded from the study.

References

1. Fischer L, Korfel A, Kiewe P, Neumann M, Jahnke K, Thiel E. Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma. Ann Hematol. 2009 Feb;88(2):133-9. Epub 2008 Aug 5. link to original article contains protocol PubMed